Diborane (B2H6) is a versatile reagent with broad applications in organic and inorganic syntheses. Because diborane is a pyrophoric gas having a flash point of about −90° C. and an autoignition temperature of about 38° C. to 51° C., borane complexes with Lewis bases are typically used instead, as they are more convenient to handle. Numerous examples of these borane complexes for use in the synthesis of pharmaceuticals and other industrial applications are well known in the art. Borane-tetrahydrofuran complex (sometimes referred to as (“BTHF” or “BTHF complex”) is one of the more widely used borane-Lewis base complexes for synthetic applications, such as hydroboration of carbon-carbon double and triple bonds, and reduction of various functional groups.
Problematically, BTHF solutions having a concentration in excess of about 2.0 moles per liter readily release diborane. In part because of instability issues, therefore, BTHF complex has been commercially available only as low concentration solutions for a number of years. Under the United States Department of Transportation (“DOT”) regulations, transportation of a package containing a material which is likely to decompose with a self-accelerated decomposition temperature (SADT) of 50° C. or less with an evolution of a dangerous quantity of heat or gas when decomposing is prohibited unless the material is stabilized or inhibited in a manner to preclude such evolution Because of the intrinsic instability and low autoignition temperature, BTHF solutions known in the art having a BTHF concentration in excess of about 1 mole per liter generally cannot meet the SADT mandated by the DOT. Aside from resulting in unacceptable SADT temperatures, diborane exhibits high vapor pressure at room temperature resulting in overpressurization of storage containers. Moreover, diborane can attack the tetrahydrofuran (“THF”) cyclic ether linkage causing ring opening thereby resulting in less pure BTHF and concomitant heat generation and container pressurization.
Another problem associated with BTHF complexes is short shelf life, especially at temperatures at or above normal room temperature of about 25° C. BTHF complexes can decompose during shipping or in storage if they are not stabilized properly, or are shipped at elevated temperature. For instance, as described in U.S. Pat. No. 6,048,985 to Burkhardt et al., the assay of a 2 molar solution of BTHF stored at room temperature (i.e., 20° C. to 25° C.) dropped from about 98% to about 16% over a period of 110 days.
In U.S. Pat. No. 3,634,277, Brown disclosed stabilizing BTHF from ring-opening ether cleavage of the tetrahydrofuran (“THF”), to some extent, with borohydride. In each of Brown's examples, however, BTHF solutions having concentrations of 1.5 to 2.0 M BTHF experienced significant decomposition of the BTHF in shelf-life/stability experiments conducted at ambient temperature for eight weeks. In addition, stabilization of BTHF with sodium borohydride does not significantly increase the SADT temperature to 50° C. or above. Also, NaB2H7, a possible by product from such stabilized solutions formed by the reaction of NaBH4 with borane, is relatively insoluble in THF and may drop out of solution as a solid precipitate thereby causing storage and material transfer problems. This is true for BTHF prepared by in situ methods or by passing highly pure diborane gas into the THF.
In the interest of conservation of resources and efficient use of reactor vessels, one would like to conduct reactions at the highest concentration possible for a particular reaction. In that regard, the low concentration of the BTHF leads to low reactor loading and inefficient use of equipment. There are several reports in the literature, however, that solutions of BTHF of greater than 1 mole per liter are unavailable as a result of the instability of such solutions. See, for example, H. C. Brown, P. Heim, N. M. Yoon JACS, 92, 1637-1646 (1970); C. F. Lane Chem. Rev., 76, 773-799 (1976); H. C. Brown, M. C. Desai, P. K. Jadhav JOC, 47, 5065-5069 (1982); M. Follet Chem. And Industry., 123-128; and K. Smith, Chem. and Industry 1987, 603-611 (1986).
Borane reagents other than BTHF complex are available in more concentrated form, but each has inherent disadvantages. For example, sulfide boranes are highly concentrated but suffer from noxious odors and amine-boranes known in the art are less reactive than BTHF. In addition, such complexing agents (amine or sulfide) are often difficult to remove from the desired product.